BACKGROUND: Risankizumab and guselkumab, inhibitors of the interleukin (IL)-23 p19 subunit, are approved for treatment of adult patients with moderate-to-severe plaque psoriasis, and both have shown superiority over placebo in randomised clinical trials. Both agents have also shown superiority to the IL-17 inhibitor secukinumab at different timepoints. We investigated the efficacy and safety of the IL-23 p19 inhibitor mirikizumab versus placebo and secukinumab for patients with moderate-to-severe plaque psoriasis. METHODS: OASIS-2 was a phase 3, multicentre, randomised, double-blind trial. We recruited participants aged at least 18 years who had a confirmed diagnosis of chronic plaque psoriasis for at least 6 months before baseline that involved at least 10% of body surface area (BSA), an absolute Psoriasis Area and Severity Index (PASI) score of at least 12, and a Static Physician's Global Assessment (sPGA) score of at least 3 at both the screening and baseline visits. We excluded patients who had an uncontrolled or unstable health condition at screening. We randomly assigned patients (4:4:4:1) to receive 250 mg mirikizumab every 4 weeks for 16 weeks (induction) then every 8 weeks from week 16 to week 52 (maintenance); 250 mg mirikizumab every 4 weeks for 16 weeks, then 125 mg mirikizumab every 8 weeks from week 16 to 52; 300 mg secukinumab once weekly up to week 4, then every 4 weeks thereafter; or placebo every 4 weeks for 16 weeks, followed by 250 mg mirikizumab every 4 weeks from week 16 to 32 and then every 8 weeks from week 32 to 52. The primary outcome was superiority of mirikizumab (250 mg induction dose) versus placebo at week 16, assessed as the proportion of patients with an sPGA score of 0 or 1 with an improvement from baseline of at least 2 points, and the proportion of patients with at least 90% improvement from baseline in PASI score (PASI 90), in the intention-to-treat-population. We assessed safety in all randomly assigned participants who received at least one dose of mirikizumab until week 16 (induction safety population) and all randomly assigned participants who received at least one dose of mirikizumab or secukinumab until week 52 (active treatment safety population). This trial is registered at ClinicalTrials.gov, NCT03535194, and is completed. FINDINGS: Between June 26, 2018, and April 2, 2019, we screened 1738 participants, of whom 1465 (84·3%) were enrolled. The mean age of participants was 46·0 years (SD 13·8), 1000 (68·3%) were men, 465 (31·7%) were women, and 1195 (81·6%) were White. Participants were randomly assigned to receive mirikizumab 250 mg for induction and maintenance (n=454 [31·0%]), mirikizumab 250 mg for induction and 125 mg for maintenance (n=451 [30·8%]), secukinumab 300 mg (n=448 [30·6%]), or placebo followed by mirikizumab (n=112 [7·6%]). Baseline characteristics were similar across treatment groups. At week 16, 721 (79·7% [95% CI 77·0-82·3]) of 905 participants in the mirikizumab 250 mg induction groups had an sPGA score of 0 or 1 versus seven (6·3% [1·8-10·7]) of 112 participants in the placebo group (p<0·0001 for superiority). At week 16, 673 (74·4% [71·5-77·2]) of 905 participants in the mirikizumab groups had PASI 90 compared with seven (6·3% [1.8-10.7]) in the placebo group (p<0·0001 for superiority). Treatment-emergent adverse events were reported with similar frequency across treatment groups during weeks 0-52. Four major adverse cardiovascular events were reported in the mirikizumab groups versus none in the placebo and secukinumab groups up to week 16, with one fatal acute myocardial infarction in a patient treated with mirikizumab, which the investigator considered to be related to the study drug. INTERPRETATION: This trial showed superiority of mirikizumab at a dose of 250 mg over placebo in patients with moderate-to-severe plaque psoriasis, with a safety profile consistent with that of the IL-23 class. The study sponsor is not pursuing licensing of mirikizumab in this patient population because of a reprioritised development strategy with a focus on gastrointestinal-related indications. FUNDING: Eli Lilly and Company.